Phase 1 study of CART-ddBCMA in relapsed or refractory multiple myeloma.
Authors: Matthew J. Frigault, Jacalyn Rosenblatt, Daniella Cook, Ha Na Cho, Gabriel D. Depinho, Emma Logan, Jessica Liegel, Yougeesh Prabhakar, Christine Cornwell, Kamalika Banerjee, Anand Rotte, Christopher Ryan Heery, David Avigan, Andrzej J. Jakubowiak, Michael Russell Bishop
Journal: Journal of Clinical Oncology (2022)

8003 Background: Chimeric Antigen Receptor (CAR) T cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated benefit in patients (pts) with relapsed and/or refractory Multiple Myeloma (RRMM). CART-ddBCMA is an autologous anti-BCMA CAR T cell therapy that utilizes a novel, synthetic binding domain, called a D-Domain, instead of a typical scFv binder. The objective of this first-in-human trial is to assess the safety and efficacy of CART-ddBCMA. Methods: This is a Phase 1, multi-center, open label, dose escalation trial for pts with RRMM who have received ≥3 prior regimens or are triple-refractory. After apheresis, bridging therapy is allowed during manufacturing. Pts receive fludarabine and cyclophosphamide (30/300 mg/m 2 /day) days -5 to -3 and CART-ddBCMA infusion on day 0. Dose escalation was performed at 100 (DL1) and 300 (DL2) x 10 6 (± 20%) CAR+T cells, followed by expansion of DL1. The primary endpoint is incidence of adverse events (AEs), including dose-limiting toxicities (DLTs). Additional endpoints are depth and duration of response (IMWG Criteria), minimal residual disease (MRD, clonoSEQ), progression-free (PFS) and overall survival (OS). Pts with 1- and 3-months follow-up were eligible for safety and efficacy analysis, respectively. Results: As of January 25, 2022, 25 pts received CART-ddBCMA, with median age 66 (range: 44-76), after a median of 5 prior lines of therapy (3-16), including 10 (40%) with extramedullary disease (EMD). Median follow-up was 9.8 (2-23.7) months. Overall, 25 pts (19 DL1; 6 DL2) were evaluable for safety and 24 (18 DL1; 6 DL2) for efficacy analysis. All pts experienced CRS, but only 1 pt (in DL2) had grade (gr) 3 CRS. All other CRS cases were gr ≤2, with no cases of gr ≥3 CRS in DL1. Four pts experienced ICANS (2, gr ≤2; 2, gr 3), with 1 gr 3 case in each of DL1 (5%) and DL2 (17%). Standard management resulted in resolution of CRS/ICANS within 30 days in all cases without sequelae. The ORR = 100%, sCR/CR rate = 67%, and ≥VGPR rate = 88%. Conversion to CR/sCR has occurred with longer follow-up, as late as month 9 in this trial. At time of data-cut 5 pts in DL1 with PR/VGPR have &lt; 9 months follow-up, with 4 (of 4 evaluable) negative at ≥10 -5 for MRD. Overall, 17 of 20 (85%) evaluable pts have achieved best MRD response of ≥10 -5 . In the dose escalation pts (i.e., those with longest follow-up, n = 12), the ORR and CR/sCR rate was 100% and 75%, respectively, despite 58% (7/12) EMD in this group. Of the first 6 pts dosed in DL1, 4 (67%) continue in ongoing sCR beyond 18 months, including 3 with EMD. Median duration of response, PFS and OS were not evaluable at the time of data-cut because 19 of 24 evaluable pts (79%) remain in ongoing response. Conclusions: CART-ddBCMA administration, to date, has demonstrated clinical activity, including 100% ORR with rates of CR/sCR and ≥VGPR of 67% and 88%, respectively. Durable responses beyond 18 months have been observed, including in pts with EMD. Clinical trial information: NCT04155749.